Abstract The glucagon response to insulin-induced hypoglycemia (IIH) is markedly impaired early in type 1 diabetes, We have previously demonstrated that this glucagon response is largely autonomically mediated in nondiabetic animals and humans. More recently we discovered an early sympathetic islet neuropathy (eSIN) in human subjects with type 1 diabetes and animal models thereof and therefore hypothesized that eSIN contributes to this glucagon impairment. Therefore, the purpose of this grant is to determine the mechanism by which 1) only sympathetic nerves are lost, 2) only from the islets and 3) only in autoimmune diabetes. The mechanism that accounts for all three is based on emerging concepts in developmental neurobiology. We propose that brain derived neurotrophic factor (BDNF), secreted by B-lymphocytes invading the islet during the development of autoimmune diabetes, shifts the balance of islet neurotrophins away from [unreadable]axonal maintenance[unreadable] via Trk receptors towards [unreadable]axonal pruning[unreadable] via the p75 pan-neurotrophin receptor (NTR), causing a selective loss of islet sympathetic nerves and thereby dysfunction of the sympathetic alpha-cell pathway. Therefore our first Specific Aim is to demonstrate the necessity of BDNF for the immune-mediated loss of islet sympathetic nerves and for the retention of islet parasympathetic nerves. We will demonstrate the presence of BDNF in the diabetic islet by immunohistochemistry and RTC-PCR. We will demonstrate its sympathetic neurotoxicity by knocking out BDNF. We will rescue islet sympathetic nerves by transducing them to ectopically express the axonal maintenance receptor that is both present on parasympathetic nerves and activated by BDNF. In our second Specific Aim we will demonstrate the necessity of B-lymphocytes by knocking them out, thus preventing the loss of islet sympathetic nerves despite the presence of immune-mediated diabetes. In our third Specific Aim we will prevent the loss of islet sympathetic nerves either by knocking out p75NTR or by transducing sympathetic neurons to express NGF that activates TrkA, their endogenous axonal maintenance receptor. Significance: Determining the mechanism of the loss of islet sympathetic nerves in type 1 diabetes will allow us to prevent or reverse that loss. Since we have previously shown that the sympathetic alpha cell pathway is activated during IIH and contributes to the glucagon response to IIH, we expect such prevention to improve this glucagon response in type 1 diabetes. Such improvement will allow more intensive treatment of patients with type 1 diabetes which will in turn help prevent the long-term complications of this disease.